Cardiomyocyte-specific deletion of GSK-3beta protected against post-MI remodeling, preserving left ventricular function at up to 8 weeks, and promoted stress-induced cardiomyocyte proliferation.
Does inducible, cardiomyocyte-specific deletion of GSK-3beta improve post-MI remodeling and cardiomyocyte proliferation in adult mice?
Cardiomyocyte-specific deletion of GSK-3beta in adult mice protects against post-MI remodeling and promotes stress-induced cardiomyocyte proliferation, suggesting a potential therapeutic target for cardiac regeneration.
RATIONALE: Numerous studies have proposed that glycogen synthase kinase (GSK)-3beta is a central regulator of the hypertrophic response of cardiomyocytes. However, all of this work has relied on overexpression of GSK-3beta, expression of constitutively active mutants, or small molecule inhibitors with documented off-target effects. Genetic loss of function approaches have not been used in the adult mouse because germ-line deletion of GSK-3beta is embryonic-lethal. OBJECTIVE: This study was designed to define the role played by GSK-3beta in pressure overload (PO)-induced hypertrophy and remodeling following myocardial infarction (MI). METHODS AND RESULTS: We used a mouse model that allows inducible, cardiomyocyte-specific deletion of GSK-3beta in the adult knockout. Surprisingly, we find that knockout mice exposed to PO induced by thoracic aortic constriction exhibit a normal hypertrophic response. Thus, in contrast to virtually all prior published studies, GSK-3beta appears to play at most a minor role in the hypertrophic response to PO stress. However, GSK-3beta does regulate post-MI remodeling because the GSK-3beta knockouts had less left ventricular dilatation and better-preserved left ventricular function at up to 8 weeks post-MI despite demonstrating significantly more hypertrophy in the remote myocardium. Deletion of GSK-3beta also led to increased cardiomyocyte proliferation following PO and MI. CONCLUSIONS: Deletion of GSK-3beta protects against post-MI remodeling and promotes stress-induced cardiomyocyte proliferation in the adult heart. These studies suggest that inhibition of GSK-3beta could be a strategy to both prevent remodeling and to promote cardiac regeneration in pathological states.
Woulfe et al. (Fri,) conducted a other in Myocardial Infarction and Pressure Overload. Cardiomyocyte-specific deletion of GSK-3beta was evaluated on Hypertrophic response, post-MI remodeling, and cardiomyocyte proliferation. Cardiomyocyte-specific deletion of GSK-3beta protected against post-MI remodeling, preserving left ventricular function at up to 8 weeks, and promoted stress-induced cardiomyocyte proliferation.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: